In 2012, there were an estimated 43,920 new cases of pancreatic cancer in the United States. The incidence nearly equals the prevalence in this deadly disease. A majority of patients present with advanced, incurable disease. Even with the most aggressive combination chemotherapy, median survival for patients with metastatic pancreatic cancer remains less than 1 year. Alternative approaches to therapy are desperately needed. A new class of antibody drugs is being developed that turn off the brakes (signals sent out by the cancer cells to evade recognition by the immune system) that are now known to inhibit cancer fighting immune cells. Unlike some cancers, pancreatic cancer does not naturally induce these cancer fighting immune cells. Therefore, vaccines are necessary to induce and expand tumor specific immune cells and likely are needed to be given together with agents designed to turn off the brakes on these immune cells to avoid inactivation when these tumor killing immune cells infiltrate the tumor. There is preclinical and preliminary clinical data to support the concept that immunotherapy can work in pancreatic cancer. To build on this progress and make the therapy more effective, this proposal will test GVAX + IPI in patients with metastatic pancreatic cancer who have been stabilized with upfront FOLFIRINOX chemotherapy versus continuing standard therapy. Integrating immunotherapy after upfront chemotherapy has several advantages. Chemotherapy can predispose cancer cells to cell death mediated by immune cells. Furthermore, chemotherapy is still the best therapy to stabilize patients with pancreatic cancer. Immunotherapy can take weeks to months to be effective and is therefore unlikely to work in patients who cannot initially be stabilized. GVAX + IPI showed promise in heavily pre-treated patients and giving it immediately after front line chemotherapy is likely to improve activity. This proposal will provide the evidence needed to conduct the final approval trial that will bring immunotherapy to patients with metastatic pancreatic cancer. If the proposal is successful, future studies will focus on expanding treatment to other pancreatic cancer populations such as those with localized and resected disease. The primary clinical objective of the protocol is to compare the overall survival (OS) of the two treatment groups. The secondary clinical objectives are to assess the safety of the treatment with particular attention to immune related adverse events, to measure CA19-9 tumor marker kinetics, to measure progression-free survival (PFS) and objective response rate by RECIST (Response Evaluation Criteria In Solid Tumors) and immune-related RECIST. Correlative immune analyses will be conducted to identify predictors of response. Peripheral blood lymphocytes (PBL) and serum will be collected to identify potential therapeutic targets and biomarkers and predictors of response and autoimmune toxicity. Induction of antigen specific T cell responses to mesothelin and changes in the mesothelin-specific T cell epitope repertoire will be correlated with OS. Lymphocyte telomere length as a predictor of response will be tested. Induction of galectin-3 antibody responses will be correlated with response. Proteomic approaches will be used on pre and post treatment sera to identify targets and biomarkers of response or toxicity. Archived tissue and pre and post treatment biopsies will be obtained to test for predictors of response and future targets for combinatorial therapy. Next generation genome sequencing will be used to identify immune responsive disease subtypes and immunohistochemistry will be used to characterize the nature of tumors and immune infiltrates in responsive subsets. Furthermore, upregulation of immune inhibitory molecules in the pre or post treatment samples may identify additional therapeutic targets.